Formation of 18F and 19F fluoroarenes bearing reactive functionalities

ABSTRACT

An iodonium compound of formula (I): 
     
       
         
         
             
             
         
       
         
         where R AR1  is a C 5-6  aryl group, bearing at least one substituent selected from formyl, thionoacyl, acylamidocarboxy, thionoester, azo, C 2-20  alkenyl, C 2-20  alkynyl, and (CH 2 ) n R C , where R C  is selected from ether, amino, azo and thioether; 
         R AR2  is a C 5-10  aryl group, optionally substituted by one or more groups selected from C 1-12  alkyl, C 5-12  aryl, C 3-12  heterocyclyl, ether, thioether, nitro, cyano and halo, and may be linked to a solid support or fluorous tag; and 
         X is a counteranion.

The present invention relates to methods of forming ¹⁸F and ¹⁹Ffluoroarenes bearing reactive functionalities, intermediates in themethods, as well as certain novel compounds which may be produced by themethods.

There is much interest in medicine in the investigation of theproperties and actions of biologically active compounds in the body. Inparticular, the pharmacokinetics and bio-distribution of an activecompound in the body is of interest during the development of new drugsand treatments. Investigations can be carried out using non-invasivemeans by administering labelled active compounds and monitoring theirdistribution, bioavailability, etc. in the body.

An example of a technique used for such investigations is PositronEmission Tomography (PET) which monitors the distribution of positronemitting isotopes such as ¹¹C, ¹⁸F, ⁶⁸Ga or compounds labelled with theposition emitting isotopes in the body. There is therefore a need in theart for methods of manufacturing such labelled compounds.

The introduction of fluorine into aromatic systems is often carried outin the art using electrophilic fluorine reagents (F⁺). Examples of suchelectrophilic reagents include F₂, XeF₂, AcOF, CF₃COOF, Selectfluor™ andN-fluorosulfonimides. Synthesis of these radiolabelled reagents isproblematic however as the source of the positron emitting isotope[¹⁸F]F₂ used to produce these reagents can only be obtained with arelatively low specific activity. [¹⁸F]Fluoride may be obtained in muchhigher amounts and in much higher specific radioactivity and istherefore the preferred reagent for the introduction of fluorine-18.

A particular compound of interest containing ¹⁸F is N-succinimidyl4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB). This has been shown to be a suitableacylation agent for radiolabelling of peptides, proteins,oligonucleotides and antibodies (Vaidyanathan, G., et al., J. Nucl. Med.33, 1535-1541 (1992); Wester, H. J., et al., Nucl. Med. Biol., 23,365-372 (1996); Wüst, F., et al., Appl. Radiat. Isot., 59, 43-48 (2003);Zijlstra, S., et al., Appl. Radiat. Isot. 58, 201-207 (2003)). Suchbioactive compounds when labelled with a [¹⁸F]fluorobenzoyl group can beuseful radiotracers for in vivo studies of physiological processes bypositron emission tomography (PET).

The synthesis of ¹⁸F and ¹⁹F fluoroarenes, using fluoride, bearingreactive functionalities, including SFB, is problematic, as the reactivefunctionality provides an alternative (usually preferred) reaction sitefor the fluoride. The result is that the process typically generates acomplex mixture of products, causing the isolation of the desiredmaterial to be difficult. Given the use of a short lived radioisotopecompounds (¹⁸F, half-life 109.7 min) this lack of selectivity presents aserious problem, as time consuming conventional purification procedurescannot be employed. However, the purity of the final compound isessential to allow direct and immediate administration of theradiotracer to a patient. In addition, alternative reaction pathways forthe radioisotope (via the reactive functionality) greatly reduces theradiochemical and specific activity of the target material. To over comethis, traditional approaches to fluorine-18 labelled materials bearingreactive functionalities involve multi-step, multi-pot procedures wherethe reactive functionality is typically introduced after theradioisotope. These additional reaction and purification steps takesignificant time given the short half-life of the radioisotope and aretherefore undesirable. The additional complexity associated withmulti-step reaction sequences using short-lived isotopes increases thehazards to the operator, is detrimental to both the radiochemical yieldand specific activity of the product and also limits the opportunitiesfor automated production of labelled material using commercialapparatus. In turn these constraints greatly restrict the translation ofsynthetic methods to GMP production of radiopharmaceuticals for clinicaluse.

To address these limitations the present inventors have developed asingle-step single-pot method of synthesising ¹⁸F and ¹⁹F fluoroarenesbearing reactive functionalities from a biaryliodonium saltintermediate.

Accordingly, a first aspect of the present invention provides aniodonium compound of formula (I):

where R^(AR1) is a C₅₋₆ aryl group, bearing at least one substituentselected from formyl, thionoacyl, acylamidocarboxy, thionoester, azo,C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, and (CH₂)_(n)R^(C), where R^(C) isselected from ether, amino, azo and thioether;

R^(AR2) is a C₅₋₁₀ aryl group, optionally substituted by one or moregroups selected from C₁₋₁₂ alkyl, C₅₋₁₂ aryl, C₃₋₁₂ heterocyclyl, ether,thioether, nitro, cyano and halo, and may be linked to a solid supportor fluorous tag (which can be used to expediate purification of thetarget material);

X is a counteranion.

A second aspect of the invention provides a method of synthesising acompound of formula II:

by fluoridating a compound of formula I.

In some embodiments, the fluoro group is ¹⁸F. The ¹⁸F will usually havean abundance of at least 90% or 95% relative to ¹⁹F. In someembodiments, the ¹⁸F will have an abundance of 99% or even 99.9%.

A third aspect of the invention provides novel compounds of formula II.

A fourth aspect of the present invention provides a method ofsynthesising a compound of formula I comprising the step of reacting acompound of formula IIIa or IIIb:

with a compound of formula IVa or IVb:

wherein Q is SnR₃, B(OH)₂ or B(OR)₂, where R is C₁₋₇ alkyl; and

W is OCOR^(W) or halo (e.g. Cl), where R^(W) is C₁₋₄ alkyl (includingfluoroalkyl).

A further aspect of the present invention provides a compound of formula(II) obtained by the method of the second aspect.

Definitions

Solid support: The term “solid support” as used herein, pertains to anysuitable solid-phase support which is insoluble in any solvents to beused in the processes of the invention but to which the linker can becovalently bound. Examples of suitable solid support include polymerssuch as polystyrene (which may be block grafted, for example withpolyethylene glycol), polyacrylamide, or polypropylene or glass orsilicon coated with such a polymer. The solid support may be in the formof small discrete particles such as beads or pins, or as a coating onthe inner surface of a cartridge or on a microfabricated vessel.

Fluorous tag: The term “fluorous tag” as used herein, pertains to aperfluoroalkyl group having from 6 to 20 carbon atoms, i.e.perfluoroC₆₋₂₀ alkyl. Examples of fluorous tags include, but are notlimited to, —C₆F₁₃, —C₅F₁₁, —C₈F₁₇ and C₁₀F₂₁. Examples of such fluoroustags are well known to those skilled in the art.

Linker: The term “linker” may be any suitable organic group which servesto space the reactive site sufficiently from the solid support structureor fluorous tag so as to maximise reactivity. The linker will be adivalent moiety and can be derived in particular from C₁₋₂₀ alkyl andC₁₋₂₀ alkoxy groups. The linker may be substituted or unsubstituted. Thelinker may also by derived from polyethylene glycol, and thus be of theformula (—C₂H₄—O—)_(n), where n is from 2 to 10. Examples of suchlinkers are well known to those skilled in the art of solid-phasechemistry.

Alkyl: The term “alkyl” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having from 1 to 20 carbon atoms (unless otherwise specified),which may be aliphatic or alicyclic, and which may be saturated orunsaturated (e.g. partially unsaturated, fully unsaturated). Thus, theterm “alkyl” includes the sub-classes alkenyl, alkynyl, cycloalkyl,cycloalkyenyl, cycloalkynyl, etc., discussed below.

In the context of alkyl groups, the prefixes (e.g. C₁₋₄, C₁₋₇, C₂₋₇,C₃₋₇, etc.) denote the number of carbon atoms, or range of number ofcarbon atoms. For example, the term “C₁₋₄ alkyl”, as used herein,pertains to an alkyl group having from 1 to 4 carbon atoms. Examples ofgroups of alkyl groups include C₁₋₄ alkyl (“lower alkyl”) and C₁₋₇alkyl. Note that the first prefix may vary according to otherlimitations; for example, for unsaturated alkyl groups, the first prefixmust be at least 2; for cyclic alkyl groups, the first prefix must be atleast 3; etc.

Examples of (unsubstituted) saturated alkyl groups include, but are notlimited to, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl(C₅), hexyl (C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀),undecyl (C₁₁) and dodecyl (C₁₂).

Examples of (unsubstituted) saturated linear alkyl groups include, butare not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl(C₄), n-pentyl (amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

Examples of (unsubstituted) saturated branched alkyl groups includeiso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),iso-pentyl (C₅), and neo-pentyl (C₅).

Alkenyl: The term “alkenyl”, as used herein, pertains to an alkyl grouphaving one or more carbon-carbon double bonds. Examples of groups ofalkenyl groups include C₂₋₄ alkenyl, C₂₋₇ alkenyl and C₂₋₁₂ alkenyl.

Examples of (unsubstituted) unsaturated alkenyl groups include, but arenot limited to, ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃),2-propenyl (allyl, —CH—CH═CH₂), isopropenyl (1-methylvinyl,—C(CH₃)═CH₂), butenyl (C₄), pentenyl (C₅), and hexenyl (C₆).

Alkynyl: The term “alkynyl”, as used herein, pertains to an alkyl grouphaving one or more carbon-carbon triple bonds. Examples of groups ofalkynyl groups include C₂₋₄ alkynyl, C₂₋₇ alkynyl and C₂₋₁₂ alkynyl.

Examples of (unsubstituted) unsaturated alkynyl groups include, but arenot limited to, ethynyl (ethinyl, —C≡CH) and 2-propynyl (propargyl,—CH₂—C≡CH).

Cycloalkyl: The term “cycloalkyl”, as used herein, pertains to an alkylgroup which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acarbocyclic ring of a carbocyclic compound, which carbocyclic ring maybe saturated or unsaturated (e.g. partially unsaturated, fullyunsaturated), which moiety has from 3 to 7 carbon atoms (unlessotherwise specified), including from 3 to 7 ring atoms. Thus, the term“cycloalkyl” includes the sub-classes cycloalkenyl and cycloalkynyl.Preferably, each ring has from 3 to 7 ring atoms. Examples of groups ofcycloalkyl groups include C₃₋₇ cycloalkyl and C₃₋₁₂ cycloalkyl.

Examples of cycloalkyl groups include, but are not limited to, thosederived from:

saturated monocyclic hydrocarbon compounds:

cyclopropane (C₃), cyclobutane (C₄), cyclopentane (C₅), cyclohexane(C₆), cycloheptane (C₇), methylcyclopropane (C₄), dimethylcyclopropane(C₅), methylcyclobutane (C₅), dimethylcyclobutane (C₆),methylcyclopentane (C₆), dimethylcyclopentane (C₇), methylcyclohexane(C₇), dimethylcyclohexane (C₈) and menthane (C₁₀);

unsaturated monocyclic hydrocarbon compounds:

cyclopropene (C₃), cyclobutene (C₄), cyclopentene (C₅), cyclohexene(C₆), methylcyclopropene (C₄), dimethylcyclopropene (C₅),methylcyclobutene (C₅), dimethylcyclobutene (C₆), methylcyclopentene(C₆), dimethylcyclopentene (C₇), methylcyclohexene (C₇) anddimethylcyclohexene (C₈);

saturated polycyclic hydrocarbon compounds:

thujane (C₁₀), carane (C₁₀), pinane (C₁₀), bornane (C₁₀), norcarane(C₇), norpinane (C₇), norbornane (C₇), adamantane (C₁₀) and decalin(decahydronaphthalene) (C₁₀); and

unsaturated polycyclic hydrocarbon compounds:

camphene (C₁₀), limonene (C₁₀) and pinene (C₁₀).

Heterocyclyl: The term “heterocyclyl”, as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a heterocyclic compound, which moiety has from 3 to 7 ring atoms(unless otherwise specified), of which from 1 to 4 are ring heteroatoms.Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4are ring heteroatoms.

In this context, the prefixes (e.g. C₃₋₇, C₅₋₆, etc.) denote the numberof ring atoms, or range of number of ring atoms, whether carbon atoms orheteroatoms. For example, the term “C₅₋₆heterocyclyl”, as used herein,pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples ofgroups of heterocyclyl groups include C₃₋₇ heterocyclyl, C₅₋₇heterocyclyl, and C₅₋₆ heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those derived from:

-   N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)    (C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅),    2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine    (C₆), dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);-   O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅),    oxole (dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆),    dihydropyran (C₆), pyran (C₆), oxepin (C₇);-   S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene)    (C₅), thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);-   O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);-   O₃: trioxane (C₆);-   N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline    (C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);-   N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅),    tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine (C₆),    tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);-   N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);-   N₂O₁: oxadiazine (C₆);-   O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,-   N₁O₁S₁: oxathiazine (C₆).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groupsinclude those derived from saccharides, in cyclic form, for example,furanoses (C₅), such as arabinofuranose, lyxofuranose, ribofuranose, andxylofuranse, and pyranoses (C₆), such as allopyranose, altropyranose,glucopyranose, mannopyranose, gulopyranose, idopyranose,galactopyranose, and talopyranose.

Spiro-C₃₋₇ cycloalkyl or heterocyclyl: The term “spiro C₃₋₇ cycloalkylor heterocyclyl” as used herein, refers to a C₃₋₇ cycloalkyl or C₃₋₇heterocyclyl ring joined to another ring by a single atom common to bothrings.

C₅₋₂₀ aryl: The term “C₅₋₂₀ aryl” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from an aromaticring atom of a C₅₋₂₀ aromatic compound, said compound having one ring,or two or more rings (e.g., fused), and having from 5 to 20 ring atoms,and wherein at least one of said ring(s) is an aromatic ring.Preferably, each ring has from 5 to 7 ring atoms.

The ring atoms may be all carbon atoms, as in “carboaryl groups” inwhich case the group may conveniently be referred to as a “C₅₋₂₀carboaryl” group.

Examples of C₅₋₂₀ aryl groups which do not have ring heteroatoms (i.e.C₅₋₂₀ carboaryl groups) include, but are not limited to, those derivedfrom benzene (i.e. phenyl) (C₆), naphthalene (C₁₀), anthracene (C₁₄),phenanthrene (C₁₄), and pyrene (C₁₆).

Alternatively, the ring atoms may include one or more heteroatoms,including but not limited to oxygen, nitrogen, and sulfur, as in“heteroaryl groups”. In this case, the group may conveniently bereferred to as a “C₅₋₂₀ heteroaryl” group, wherein “C₅₋₂₀” denotes ringatoms, whether carbon atoms or heteroatoms. Preferably, each ring hasfrom 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

Examples of C₅₋₂₀ heteroaryl groups include, but are not limited to, C₅heteroaryl groups derived from furan (oxole), thiophene (thiole),pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole),triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole,tetrazole and oxatriazole; and C₆ heteroaryl groups derived fromisoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine(1,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine)and triazine.

The heteroaryl group may be bonded via a carbon or hetero ring atom.

Examples of C₅₋₂₀ heteroaryl groups which comprise fused rings, include,but are not limited to, C₉ heteroaryl groups derived from benzofuran,isobenzofuran, benzothiophene, indole, isoindole; C₁₀ heteroaryl groupsderived from quinoline, isoquinoline, benzodiazine, pyridopyridine; C₁₄heteroaryl groups derived from acridine and xanthene.

The above alkyl, heterocyclyl, and aryl groups, whether alone or part ofanother substituent, may themselves optionally be substituted with oneor more groups selected from themselves and the additional substituentslisted below.

-   Azo: —N₃-   Halo: —F, —Cl, —Br, and —I.-   Hydroxy: —OH.-   Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇    alkyl group (also referred to as a C₁₋₇ alkoxy group), a C₃₋₂₀    heterocyclyl group (also referred to as a C₃₋₂₀ heterocyclyloxy    group), or a C₅₋₂₀ aryl group (also referred to as a C₅₋₂₀ aryloxy    group), preferably a C₁₋₇ alkyl group.-   Nitro: —NO₂.-   Cyano (nitrile, carbonitrile): —CN.-   Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example,    H, a C₁₋₇ alkyl group (also referred to as C₁₋₇ alkylacyl or C₁₋₇    alkanoyl), a C₃₋₂₀ heterocyclyl group (also referred to as C₃₋₂₀    heterocyclylacyl), or a C₅₋₂₀ aryl group (also referred to as C₅₋₂₀    arylacyl), preferably a C₁₋₇ alkyl group. Examples of acyl groups    include, but are not limited to, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃    (propionyl), —C(═O)C(CH₃)₃ (butyryl), and —C(═O)Ph (benzoyl,    phenone).-   Thionoacyl: —C(═S)R, where R is a thionoacyl substituent, for    example, H, a C₁₋₇ alkyl group (also referred to as C₁₋₇    alkylthionoacyl), a C₃₋₂₀ heterocyclyl group (also referred to as    C₃₋₂₀ heterocyclylthionoacyl), or a C₅₋₂₀ aryl group (also referred    to as C₅₋₂₀ arylthionoacyl), preferably a C₁₋₇ alkyl group. Examples    of thionoacyl groups include, but are not limited to, —C(═S)CH₃,    —C(═S)CH₂CH₃, —C(═S)C(CH₃)₃, and —C(═S)Ph.-   Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.-   Carboxy (carboxylic acid): —COOH.-   Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,    wherein R is an ester substituent, for example, a C₁₋₇ alkyl group,    a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇    alkyl group (a C₁₋₇ alkyl ester). Examples of ester groups include,    but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃,    and —C(═O)OPh.-   Thionoester: —C(═S)OR, wherein R is an thionoester substituent, for    example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀    aryl group, preferably a C₁₋₇ alkyl group (a C₁₋₇ alkyl ester).    Examples of ester groups include, but are not limited to,    —C(═S)OCH₃, —C(═S)OCH₂CH₃, —C(═S)OC(CH₃)₃, and —C(═S)OPh.-   Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide):    —C(═O)NR¹R², wherein R¹ and R² are independently amino substituents,    as defined for amino groups. Examples of amido groups include, but    are not limited to, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂,    —C(═O)NHCH₂CH₃, and —C(═O)N(CH₂CH₃)₂, as well as amido groups in    which R¹ and R², together with the nitrogen atom to which they are    attached, form a heterocyclic structure as in, for example,    piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and    piperazinylcarbonyl.-   Amino: —NR¹R², wherein R¹ and R² are independently amino    substituents, for example, hydrogen, a C₁₋₇ alkyl group (also    referred to as C₁₋₇ alkylamino or di-C₁₋₇ alkylamino), a C₃₋₂₀    heterocyclyl group, or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇    alkyl group, or, in the case of a “cyclic” amino group, R¹ and R²,    taken together with the nitrogen atom to which they are attached,    form a heterocyclic ring having from 4 to 8 ring atoms. Examples of    amino groups include, but are not limited to, —NH₂, —NHCH₃,    —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic    amino groups include, but are not limited to, aziridinyl,    azetidinyl, pyrrolidinyl, piperidino, piperazinyl,    perhydrodiazepinyl, morpholino, and thiomorpholino. The cylic amino    groups may be substituted on their ring by any of the substituents    defined here, for example carboxy, carboxylate and amido.-   Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amide    substituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀    heterocyclyl group, or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇    alkyl group, most preferably H, and R² is an acyl substituent, for    example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀    aryl group, preferably a C₁₋₇ alkyl group. Examples of acylamide    groups include, but are not limited to, —NHC(═O)CH₃, —NHC(═O)CH₂CH₃,    and —NHC(═O)Ph. R¹ and R² may together form a cyclic structure, as    in, for example, succinimidyl, maleimidyl, and phthalimidyl:

-   Acylamidocarboxy: —C(═O)ONR¹C(═O)R², wherein R¹ is an amide    substituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀    heterocyclyl group, or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇    alkyl group, most preferably H, and R² is an acyl substituent, for    example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀    aryl group, preferably a C₁₋₇ alkyl group. Examples of    acylamidocarboxy groups include, but are not limited to,    —C(═O)ONHC(═O)CH₃, —C(═O)ONHC(═O)CH₂CH₃, and —C(═O)ONHC(═O)Ph. R¹    and R² may together form a cyclic structure, as in, for example,    succinimidylcarboxy, maleimidylcarboxy, and phthalimidylcarboxy:

-   Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently amino    substituents, as defined for amino groups, and R¹ is a ureido    substituent, for example, hydrogen, a C₁₋₇alkyl group, a    C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen    or a C₁₋₇alkyl group. Examples of ureido groups include, but are not    limited to, —NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂,    —NMeCONH₂, —NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, —NMeCONEt₂ and    —NHC(═O)NHPh.-   Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy    substituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl    group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group.    Examples of acyloxy groups include, but are not limited to,    —OC(═O)CH₃ (acetoxy), —OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph,    —OC(═O)C₆H₄F, and —OC(═O)CH₂Ph.-   Thiol: —SH.-   Thioether (sulfide): —SR, wherein R is a thioether substituent, for    example, a C₁₋₇ alkyl group (also referred to as a C₁₋₇ alkylthio    group), a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,    preferably a C₁₋₇ alkyl group. Examples of C₁₋₇ alkylthio groups    include, but are not limited to, —SCH₃ and —SCH₂CH₃.-   Sulfoxide (sulfinyl): —S(═O)R, wherein R is a sulfoxide substituent,    for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a    C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples of    sulfoxide groups include, but are not limited to, —S(═O)CH₃ and    —S(═O)CH₂CH₃.-   Sulfonyl (sulfone): —S(═O)₂R, wherein R is a sulfone substituent,    for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a    C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples of sulfone    groups include, but are not limited to, —S(═O)₂CH₃ (methanesulfonyl,    mesyl), —S(═O)₂CF₃, —S(═O)₂CH₂CH₃, and 4-methylphenylsulfonyl    (tosyl).-   Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² are    independently amino substituents, as defined for amino groups.    Examples of amido groups include, but are not limited to, —C(═S)NH₂,    —C(═S)NHCH₃, —C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.-   Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as    defined for amino groups, and R is a sulfonamino substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of    sulfonamino groups include, but are not limited to, —NHS(═O)₂CH₃,    —NHS(═O)₂Ph and —N(CH₃)S(═O)₂C₆H₅.-   Siloxy (silyl ether): —OSiR₃, where R is H or a C₁₋₇alkyl group.    Examples of silyloxy groups include, but are not limited to, —OSiH₃,    —OSiH₂(CH₃), —OSiH(CH₃)₂, —OSi(CH₃)₃, —OSi(Et)₃, —OSi(iPr)₃,    —OSi(tBu)(CH₃)₂, and —OSi(tBu)₃.

As mentioned above, the groups that form the above listed substituentgroups, e.g. C₁₋₇ alkyl, C₃₋₂₀ heterocyclyl and C₅₋₂₀ aryl, maythemselves be substituted. Thus, the above definitions cover substituentgroups which are substituted.

All the documents referenced herein are incorporated by reference.

Further Preferences and Embodiments

First Aspect

R^(AR1)

R^(AR1) is a C₅₋₆ aryl group, bearing at least one substituent selectedfrom formyl, thionoacyl, acylamidocarboxy, thionoester, azo, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, and (CH₂)_(n)R^(C), where R^(C) is selected fromether, amino, azo and thioether.

In some embodiments, the C₅₋₆ aryl group may bear a single substituent.In other embodiments, the C₅₋₆ aryl group may bear two, three or foursubstituents.

If R^(AR1) is a heteroaryl group it may be selected from a C₅ heteroarylgroup derived from: furan (oxole), thiophene (thiole), pyrrole (azole),imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole;or from a C₆ heteroaryl group derived from: isoxazine, pyridine (azine),pyridazine (1,2-diazine), pyrimidine (1,3-diazine; e.g., cytosine,thymine, uracil), pyrazine (1,4-diazine) and triazine.

If R^(AR1) is a carboaryl group, it is phenyl. In these embodiments,R^(AR1) can be represented as:

wherein each of R^(C1), R^(C2), R^(C3), R^(C4) and R^(C5) are selectedfrom H and formyl, thionoacyl, acylamidocarboxy, thionoester, azo, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, and (CH₂)_(n)R^(C), where R^(C) is selected fromether, amino, azo and thioether, provided that at least one of R^(C1),R^(C2), R^(C3), R^(C4) and R^(C5) is not H.

In some embodiments, which may be preferred, one of R^(C1), R^(C2),R^(C3), R^(C4) and R^(C5) is selected from formyl, thionoacyl,acylamidocarboxy, thionoester and (CH₂)_(n)R^(C), where R^(C) isselected from ether, azo, amino and thioether, whilst the remaininggroups are H. In other embodiments, two, three or four of R^(C1),R^(C2), R^(C3), R^(C4) and R^(C5) is selected from formyl, thionoacyl,acylamidocarboxy, thionoester and (CH₂)_(n)R^(C), where R^(C) isselected from ether, azo, amino and thioether, whilst the remaininggroups are H.

The substituents for R^(AR1) may, in some embodiments, be selected fromformyl, carboxy, acylamidocarboxy (e.g. CO₂N(COCH₂)₂), CH₂OH and CH₂NH₂.

In some embodiments, R^(AR1) bears a single substituent that is anacylamidocarboxy group. Of particular interest are groups in which theamide and acyl substituent form a cyclic structure, for example:

Of these groups, succinimidylcarboxy may be preferred.

If R^(AR1) in these embodiments is phenyl and its sole substituent issuccinimidylcarboxy, then the compound produced by fluoridation isN-succinimidyl-fluorobenzoate, and may beN-succinimidyl-2-fluorobenzoate, N-succinimidyl-3-fluorobenzoate orN-succinimidyl-4-fluorobenzoate in which the fluoro group may belabelled or unlabelled.

$\frac{R^{{AR}\; 2}}{R^{{AR}\; 2}}$is a C₅₋₁₀ aryl group that is optionally substituted by one or moregroups selected from C₁₋₁₂ alkyl, C₅₋₁₂ aryl, C₃₋₁₂ heterocyclyl, ether,thioether, nitro, cyano and halo. R^(AR2) may be linked to a solidsupport or fluorous tag.

If R^(AR2) is a heteroaryl group it may be selected from a C₅ heteroarylgroup derived from: furan (oxole), thiophene (thiole), pyrrole (azole),imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole;or from a C₆ heteroaryl group derived from: isoxazine, pyridine (azine),pyridazine (1,2-diazine), pyrimidine (1,3-diazine; e.g., cytosine,thymine, uracil), pyrazine (1,4-diazine) and triazine. Of thesethiophenyl and furanyl may be preferred, and thiophenyl (e.g.thiophen-2-yl, thiophen-3-yl) may be more preferred. These groups may besubstituted or unsubstituted. In some embodiments, it is preferred thatthey are not substituted.

If R^(AR2) is a carboaryl group, it is phenyl.

Preferred substituents for R^(AR2) may include ethers, thioethers andamines. Of these ethers (for example, C₁₋₇ alkoxy (methoxy, ethoxy)) maybe preferred.

Without wishing to be bound by theory, having R^(AR2) as a C₅ heteroarylgroup results in a particularly stable iodonium salt of formula I, whichwhen fluorinated under the reaction conditions described herein producesa high yield. This is though to be especially the case when thefluorination is by ¹⁸F which proceeds with a good radiochemical yield.

X

X is a counteranion. It may be selected from CF₃COO, TsO, MsO, NsO, TfO,NO₃, Br, Cl and SO₄. It may also be selected from BAr₄, where Arrepresents a C₅₋₂₀ aryl group, such as a C₅₋₇ aryl group (e.g. phenyl,tolyl). The aryl group may itself be substituted, as described above.

In some embodiments, the counteranion may be trifluoroacetate,trifluoromethane sulfonate or tosyl. Of these trifluoroacetate is themost preferred, with TfO also being preferred.

Second Aspect

The second aspect of the invention provides a method of synthesising acompound of formula II:

by fluoridating a compound of formula I. The fluoridation can involvethe introduction of ¹⁸F or ¹⁹F. The source of fluoride can providefluoride as labelled (for example [¹⁸F]F⁻ or unlabelled fluoride.Examples of fluoride sources are NaF, KF, CsF, tetraalkylammoniumfluoride, or tetraalkylphosphonium fluoride. Examples of [¹⁸F] fluoridesources include Na¹⁸F, K¹⁸F, Cs¹⁸F, tetraalkylammonium [¹⁸F] fluoride,or tetraalkylphosphonium [¹⁸F] fluoride. To increase the reactivity ofthe fluoride, a phase transfer catalyst such as an aminopolyether orcrown ether for example, 4,7,13,16,21,24hexaoxa-1,10-diazabicyclo[8,8,8] hexacosane (Kryptofix 2.2.2) may beadded and the reaction performed in a suitable solvent.

These conditions give reactive fluoride ions. Optionally, a free radicaltrap may be used to improve fluoridation yields, as described in WO2005/061415. The term “free radical trap” is defined as any agent thatinteracts with free radicals and inactivates them. A suitable freeradical trap for this purpose may be selected from2,2,6,6-Tetramethylpiperidine-N-Oxide (TEMPO), 1,2-diphenylethylene(DPE), ascorbate, para-amino benzoic acid (PABA), a-tocopherol,hydroquinone, di-t-butyl phenol, β-carotene and gentisic acid. Preferredfree radical traps for use In the method of the invention are TEMPO andDPE, with TEMPO being most preferred.

The treatment with fluoride may be effected in the presence of asuitable organic solvent such; as acetonitrile, dimethylformamide,dimethylsulphoxide, dimethylacetamide, tetrahydrofuran, dioxan,1,2-dimethoxyethane, sulpholane, N-methylpyrolidininone, or in an ionicliquid such as an imidazolium derivative (for example1-ethyl-3-methylimidazolium hexafluorophosphate), a pyridiniumderivative (for example, 1-butyl-4methylpyridinium tetrafluoroborate), aphosphonium compound, or tetralkylammonium compound at a non-extremetemperature, for example, 15° C. to 150° C., preferably at elevatedtemperature, such as 80° C. to 150° C., for example around 110° C. Otherpossible organic solvents include tert-amyl alcohol, trifluoroethanoland hexfluoroisopropanol. The reaction may be carried out at upto 250°C.

In one aspect of the invention, the solvent used is dry, meaning thatthe level of water present is 1000 ppm or less, more suitably 600 ppm orless, and preferably 100 ppm or less.

Third Aspect

N-succinimidyl-2-fluorobenzoate, N-succinimidyl-3-fluorobenzoate,N-succinimidyl-2-[¹⁸F]fluorobenzoate andN-succinimidyl-3-[¹⁸F]fluorobenzoate may be embodiments of the thirdaspect of the invention.

Fourth Aspect

W may be acetate or trifluoroacetate.

Q may be SnBu₃ or SnMe₃.

The embodiments and preferences expressed above may be combined togetherin any possible combination and may be combined across the variousaspects, as appropriate.

The invention will now be further described by the following examples.

EXAMPLES

General Methods

Reactions requiring anhydrous conditions were performed using oven-driedglassware and conducted under a positive pressure of dinitrogen.Anhydrous solvents were prepared in accordance with standard protocols,or alternatively purchased from Aldrich in Sure/Seal™ bottles. Infraredspectra were recorded on a Nicolet Avatar 370DTGS FT-IR spectrometerwith internal calibration. ¹H, ¹³C and COSY NMR spectra were recorded ona Bruker Avance 300 spectrometer with residual protic solvent as aninternal reference. ¹⁹F NMR were recorded on a Jeol λ 500 MHzspectrometer with CFCl₃ as an external reference. Elemental analyseswere carried out at London Metropolitan University. Mass spectra andaccurate masses were recorded at the EPSRC Mass Spectrometry Service,Swansea. Melting points were recorded on a Gallenkamp MF-370 meltingpoint apparatus and are uncorrected.

Example 1 Synthesis of(4-((2,5-Dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(thiophen-2-yl)iodoniumtrifluoroacetate (4)

(a) N-Succinimidyl-4-iodobenzoate (2)

To the solution of 4-iodobenzoic acid (1)(1.24 g, 5.0 mmol) andtriethylamine (0.71 mL, 5.0 mmol) in DMF (30 mL) was added TSTU (1.51 g,5.0 mmol). The solution was stirred at room temperature for 2 hours. Thereaction was quenched by addition of 10% HCl (50 mL). The precipitatewas collected by filtration, washed with water and dried in vacuo toyield the title compound (2) as a white powder (1.42 g, 82%); m.p.130-132° C.; v_(max)/cm⁻¹(neat) 1769 (C═O, ester), 1719 (C═O, amide);(Found C, 38.40; H, 2.41; N, 4.15. C₁₁H₈INO₄ requires C, 38.28; H, 2.34;N, 4.06%.); δ_(H) (300 MHz, CDCl₃) 7.92 (2H, d, J 12.0 Hz, H_(2/6)),7.85 (2H, d, J 12.0 Hz, H_(3/5)), 2.92 (4H, s, CH₂); δ_(c) (75 MHz,CDCl₃) 169.0 (OCO), 162.0 (NCO), 138.7 (C_(2/6)), 132.0(C_(3/5)), 125.3(C₁), 103.3(C₄), 26.0 (CH₂); m/z (E.I.), 345 (M⁺, 5%), 231 (100%), 202(20%), and 76 (48%); HRMS for C₁₁H₈INO₄ requires 344.9493 found344.9493.

(b) N-Succinimidyl-4-tributylstannyl benzoate (3)

A solution of N-succinimidyl-4-iodobenzoate (2)(1.42 g, 4.1 mmol) andbis(tributyltin) (4.0 mL, 8.2 mmol) in anhydrousN,N-dimethylformamide/toluene (1:1, 70 mL) was degassed with nitrogenfor 15 minutes before the addition of Pd(PPh₃)₄ (56 mg, 0.1 mmol). Thesolution was refluxed for 24 hours under nitrogen. The reaction wasquenched by addition of water (100 mL). The mixture was extracted withdiethyl ether (3×50 mL) and the combined organic phases were dried overMgSO₄. The solvents were removed in vacuo and the crude material waspurified by column chromatography on silica, eluting with hexane anddiethyl ether (3:2 then 2:3) to yield the title compound as a colourlessoil (1.01 g, 48%); (Found C, 54.28; H, 6.90; N, 2.68. C₂₃H₃₅NO₄Snrequires C, 54.35; H, 6.94; N, 2.76%.); v_(max)/cm⁻¹(neat) 2922 (C—H),1769 (O═CO), 1739 (O═CN); δ_(H) (300 MHz, CDCl₃) 8.05 (2H, d, J 9.0 Hz,H_(2/6)), 7.67 (2H, d, J 9.0 Hz, H_(3/5)), 2.93 (4H, s, COCH₂×2),1.69-1.44 (6H, m, SnCH₂CH ₂), 1.40-1.33 (6H, m, CH ₂CH₃), 1.18-1.12 (6H,m, SnCH ₂), 0.88 (9H, t, J 6.0 Hz, CH₂CH ₃); δ_(c) (75 MHz, CDCl₃) 169.3(OCO), 162.7 (NCO), 153.4 (C₁), 137.1 (C_(2/6)), 129.4 (C_(3/5)), 125.1(C₄), 29.4 (SnCH₂ CH₂), 27.5 (CH₂CH₃), 26.0 (COCH₂), 13.8 (CH₂CH₂ CH₃),10.2 (SnCH₂); m/z (E.I.), 523 (M⁺, 32%), 304 (14%), 237 (32%), 101(100%), 84 (66%), and 72 (65%); HRMS for C₂₃H₃₅NO₄ ¹¹⁶Sn requires523.1922 found 523.1919.

(c)(4-((2,5-Dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(thiophen-2-yl)iodoniumtrifluoroacetate (4)

To a solution of diacetoxyiodo-2-thiophene (0.72 g, 2.0 mmol) inanhydrous dichloromethane (25 mL) was added trifluoro acetic acid (0.31mL, 4.0 mmol) dropwise at −30° C. under nitrogen. After 30 minutes, thesolution was warmed to room temperature and stirred for another hour.When the solution was recooled to 30° C., ethyl 4-tributylstannanyl(1.01 g, 2.0 mmol) was added. The solution was warmed to roomtemperature overnight. The solvent was removed in vacuo and the crudematerial was purified by recrystallisation from acetonitrile to yieldthe title compound (4) as colourless needles (0.37 g, 26%); m.p.106-108° C.; (Found C, 37.84; H, 2.04; N, 2.50. C₁₇H₁₅₁F₃INO₆S requiresC, 37.73; H, 2.05; N, 2.59%.); v_(max)/cm⁻¹(neat) 1732 (ester), 1645(amide); δ_(H) (300 MHz, DMF-d₇) 8.60 (2H, d, J 9.0 Hz, H_(2/6)), 8.25(2H, d, J 9.0 Hz, H_(3/5)), 8.22 (1H, dd, J 6.0 Hz, J′ 3.0 Hz, H′₅),8.06 (1H, d, J 3.0 Hz, J′9.0 Hz, H′₃), 7.26 (1H, d, J 6.0 Hz, J′ 9.0 Hz,H′₄), 2.97 (4H, s, 2×CH₂); δ_(c) (125 MHz, DMF-d₇) 170.2 (OCO), 162.0(OCN), 141.0 (C′₅), 137.4 (C′₃), 135.7 (C_(2/6)), 132.6 (C_(3/5)), 129.8(C′₄), 127.8 (C₄), 127.2 (C₁), 102.6 (C′₂), 26.0 (CH₂); m/z (ES.I.), 429(MH⁺, 12%), 428 (M⁺, 100%), and 331 (7%); HRMS for C₁₅H₁₁INO₄S⁺ requires427.9448 found 427.9444.

Example 2 Synthesis of N-succinimidyl-4-fluorobenzoate (5)

To a mixture of CsF (7 mg, 0.05 mmol), TEMPO (1 mg, 10 mol %) andiodonium salt (0.05 mmol) in anhydrous N,N-dimethylformamide (3 mL) andthe internal standard 3-trifluoromethyl anisole (0.05 mL, 1 mmol/mL indry DMF) were added in a long glass tube flushed with nitrogen. Thesolution was heated at 130° C. for 1.5 hours under nitrogen. When themixture was cooled to room temperature, a sample (0.3 mL) was taken anddiluted with N,N-dimethylformamide (0.4 mL) and analysed by ¹⁹F NMR.

Temperature (° C.) 70 90 110 130 Yield trace 7% 10% 6% CsF(1.0 equiv.)

Example 3 Synthesis of N-succinimidyl-4-[¹⁸F]fluorobenzoate (5′)

NCA [¹⁸F]fluoride was automatically dried by azeotropic evaporation at110° C. using a solution of K₂CO₃ (3 mg, 26 μmol) and Kryptofix_(2.2.2)(16 mg, 42 μmol) in acetonitrile/water (6.5:1) under argon and thenredissolved in anhydrous acetonitrile (0.5 mL). An aliquot (˜100 MBq)was taken and the acetonitrile was evaporated manually at 110° C. underargon to which a solution of the iodonium salt (4)(2.7 mg, 5 μmol) andTEMPO (1 mg) in DMF (0.1 mL) was added. The reaction was heated at 130°C. for 5 minutes. The reaction was quenched by addition of water (50μL). An aliquot (20 μL) was taken and analysed by reversed-phase radioHPLC (Phenomenex PolymerX, 50 mm) using 2 mL/min acetonitrile/water(25/75) as eluent and radiochemical yields were also determined byradio-HPLC 4-23% (n=8).

Example 4 (a)(4-((2,5-Dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(4-methoxyphenyl)iodoniumtrifluoroacetate (6)

To a solution of diacetoxyiodo-4-methoxybenzene (0.64 g, 1.8 mmol) inanhydrous dichloromethane (25 mL) was added trifluoro acetic acid (0.28mL, 3.6 mmol) dropwise at −30° C. under nitrogen. After 30 minutes, thesolution was warmed to room temperature and stirred for another hour.When the solution was recooled to −30° C.,N-succinimidyl-4-tributylstannyl benzoate (3)(0.93 g, 1.8 mmol) wasadded. The solution was warmed to room temperature overnight. Thesolvent was removed in vacuo and the crude material was purified bycolumn chromatography on silica, eluting with dichloromethane andmethanol (15:1) and then recrystallisation from dichloromethane andpetrol to yield the title compound (6) as colourless needles (0.38 g,37%); m.p. 102-103° C.; (Found C, 42.56; H, 2.74; N, 2.38. C₂₀H₁₅F₃INO₇requires C, 42.50; H, 2.67; N, 2.48%.); v_(max)/cm⁻¹(neat) 1734 (ester),1654 (amide); δ_(H) (500 MHz, DMSO-d₆) 8.40 (2H, d, J 9.0 Hz, H_(3/5)),8.23 (2H, d, J 9.0 Hz, H′_(3/5)), 8.16 (1H, d, J 9.0 Hz, H_(2/6)), 7.11(2H, d, J 9.0 Hz, H′_(2/6)), 3.81 (3H, s, CH₃), 2.84 (4H, s, CH₂CH₂);δ_(c) (125 MHz, CDCl₃) 169.9 (OCO), 163.6 (OCN), 161.0 (C′₄), 137.9(C′_(2/6)), 134.9 (C_(3/5)), 133.3 (C′_(3/5)), 128.8 (C₄), 123.1(C₁),118.5 (C_(2/6)), 104.2 (C′₁), 56.0 (OCH₃), 26.0 (CH₂); m/z (ES.I.), 452(M⁺, 100%), 369 (20%), 355 (60%), and 341 (23%); HRMS for C₁₈H₁₅INO₅ ⁺requires 451.9989 found 451.9987.

(b)(4-((2,5-Dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(2-methoxyphenyl)iodoniumtrifluoroacetate (7)

To a solution of diacetoxyiodo-2-methoxybenzene (0.77 g, 2.2 mmol) inanhydrous dichloromethane (25 mL) was added trifluoro acetic acid (0.33mL, 4.4 mmol) dropwise at −30° C. under nitrogen. After 30 minutes, thesolution was warmed to room temperature and stirred for another hour.When the solution was recooled to −30° C.,N-succinimidyl-4-tributylstannyl benzoate (3)(1.11 g, 2.2 mmol) wasadded. The solution was warmed to room temperature overnight. Thesolvent was removed in vacuo and the crude material was purified bycolumn chromatography on silica, eluting with dichloromethane andmethanol (12:1) to yield the title compound (7) as colourless needles(0.44 g, 36%); m.p. 142-144° C.; (Found C, 42.57; H, 2.68; N, 2.37.C₂₀H₁₅F₃INO₇ requires C, 42.50; H, 2.67; N, 2.48%.); v_(max)/cm⁻¹(neat)1660 (ester), 1632 (amide); δ_(H) (300 MHz, DMSO-d₆) 8.33 (1H, d, J 9.0Hz, H′₃), 8.15 (2H, d, J 6.0 Hz, H_(3/5)), 7.66 (1H, t, J 9.0 Hz, H′₅),7.50 (2H, d, J 6.0 Hz, H_(2/6)), 7.32 (1H, d, J 9.0 Hz, H′₆), 7.10 (1H,t, J 9.0 Hz, H′₄), 3.94 (3H, s, CH₃), 2.97 (2H, s, CH₂), 2.82 (2H, s,CH₂); δ_(c) (125 MHz, CDCl₃) 169.0 (OCO), 169.0 (OCN), 157.0 (C′₂),140.3 (C₄), 137.9 (C′₃), 135.6 (C_(3/5)), 135.5 (C′₅), 130.3 (C_(2/6)),124.0 (C′₄), 117.0 (C₁), 118.5 (C′₆), 107.3 (C′₁), 57.6 (OCH₃), 39.8(CH₂), 34.9 (CH₂); m/z (ES.I.), 452 (M⁺, 20%), 227 (92%), 133 (100%), 92(65%), and 60 (57%); HRMS for C₁₈H₁₅INO₅ ⁺ requires 451.9989 found451.9984.

Example 5[4-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-phenyl]-phenyl-iodoniumtrifluoroacetate (8)

To a solution of diacetoxyiodo-4-methoxybenzene (2.03 g, 4.0 mmol) inanhydrous dichloromethane (40 mL) was added trifluoro acetic acid (0.62mL, 8.0 mmol) dropwise at −30° C. under nitrogen. After 30 minutes, thesolution was warmed to room temperature and stirred for another hour.When the solution was recooled to −30° C.,N-succinimidyl-4-tributylstannyl benzoate (3)(2.03 g, 4.0 mmol) wasadded. The solution was warmed to room temperature overnight. Thesolvent was removed in vacuo and the crude material was purified bycolumn chromatography on silica, eluting with dichloromethane andmethanol (20:1) and then recrystallisation from dichloromethane andpetrol to yield the title compound (8) as colourless needles (0.40 g,20%); m.p. 95-97° C.; (Found C, 43.87; H, 2.49; N, 2.66. C₁₉H₁₃F₃INO₆requires C, 43.95; H, 2.52; N, 2.70%.); v_(max)/cm⁻¹(neat) 1736 (ester),1650 (amide); δ_(H) (300 MHz, DMSO-d₆) 8.48 (2H, d, J 9.0 Hz, H_(3/5)),8.30 (2H, d, J 6.0 Hz, H′_(2/6)), 8.19 (2H, d, J 9.0 Hz, H_(2/6)), 7.69(1H, t, J 6.0 Hz, H′₄), 7.55 (2H, t, J 6.0 Hz, H′_(3/5)), 2.89 (4H, s,CH₂); δ_(c) (125 MHz, CDCl₃) 169.0 (OCO), 161.0 (OCN), 135.6 (C′_(2/6)),135.4 (C_(2/6)), 133.3 (C_(3/5)), 132.7 (C′_(3/5)), 130.5 (C₄), 129.0(C′₄), 123.1 (C₁), 116.6 (C′₁), 26.5 (CH₂); m/z (ES.I.), 422 (M⁺, 60%),325 (100%), and 198 (10%); HRMS for C₁₇H₁₃INO₄ ⁺ requires 421.9884 found421.9884.

Under the reaction conditions of Example 2 above, trace amounts ofN-succinimidyl-4-fluorobenzoate (5) were produced.

Example 6 Synthesis of(4-((2,5-Dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(thiophen-2-yl)iodoniumtrifluoroacetate (12)

(a) N-Succinimidyl-3-iodobenzoate (10)

To the solution of 3-iodobenzoic acid (9)(4.42 g, 17.8 mmol) andtriethylamine (2.53 mL, 17.8 mmol) in DMF (80 mL) was added TSTU (5.38g, 17.8 mmol). The solution was stirred at room temperature for 4 hours.The reaction was quenched by addition of 10% HCl (150 mL). Theprecipitate was collected by filtration, washed with water and dried invacuo to yield the title compound (10) as a white powder (4.20 g, 69%);v_(max)/cm⁻¹(neat) 1770 (C═O, ester), 1728 (C═O, amide); (Found C,38.37; H, 2.26; N, 4.08. C₁₁H₈INO₄ requires C, 38.28; H, 2.34; N,4.06%.); δ_(H) (300 MHz, CDCl₃) 8.35 (1H, s, H₂), 8.21 (1H, d, J 9.0 Hz,H₆), 8.11 (1H, d, J 6.0 Hz, H₄), 7.46 (1H, dd, J 9.0 Hz, J′6.0 Hz, H₅),2.90 (4H, s, CH₂); δ_(c) (75 MHz, CDCl₃) 170.2 (OCO), 160.9 (NCO), 144.3(C₄), 138.2 (C₂), 131.8 (C₅), 129.6 (C₆), 127.1 (C₁), 95.3 (C₃), 26.0(CH₂); m/z (E.I.), 345 (M⁺, 10%), 231 (100%), 202 (30%), and 76 (68%);HRMS for C₁₁H₈INO₄ requires 344.9493 found 344.9495.

(b) N-Succinimidyl-3-tributylstannyl benzoate (11)

A solution of N-succinimidyl-3-iodobenzoate (10)(4.00 g, 11.6 mmol) andbis(tributyltin) (11.3 mL, 23.2 mmol) in anhydrousN,N-dimethylformamide/toluene (1:1, 140 mL) was degassed with nitrogenfor 15 minutes before the addition of Pd(PPh₃)₄ (158 mg, 0.3 mmol). Thesolution was refluxed for 24 hours under nitrogen. The reaction wasquenched by addition of water (150 mL). The mixture was extracted withdiethyl ether (3×50 mL) and the combined organic phases were dried overMgSO₄. The solvents were removed in vacuo and the crude material waspurified by column chromatography on silica, eluting with hexane anddiethyl ether (3:2) to yield the title compound as a colourless oil(2.74 g, 46%); (Found C, 54.30; H, 6.91; N, 2.72. C₂₃H₃₅NO₄Sn requiresC, 54.35; H, 6.94; N, 2.76%.); v_(max)/cm⁻¹(neat) 2922 (C—H), 1770(O═CO), 1740 (O═CN); δ_(H) (300 MHz, CDCl₃) 8.22 (1H, s, H₂), 8.07 (1H,d, J 6.0 Hz, H₆), 7.78 (1H, d, J 6.0 Hz,), 7.49 (1H, t, J 6.0 Hz, H₅),2.94 (4H, s, COCH₂×2), 1.60-1.50 (6H, m, SnCH₂CH ₂), 1.40-1.31 (6H, m,CH ₂CH₃), 1.16-1.08 (6H, m, SnCH ₂), 0.86 (9H, t, J 6.0 Hz, CH₂CH ₃);δ_(c) (75 MHz, CDCl₃) 169.2 (OCO), 162.8 (NCO), 144.05 (C₁), 143.1 (C₂),138.5 (C₆), 130.3 (C₄), 128.3 (C₅), 125.2 (C₃), 29.4 (SnCH₂ CH₂), 27.6(CH₂CH₃), 26.1 (COCH₂), 13.5 (CH₂CH₂ CH₃), 10.2 (SnCH₂); m/z (E.I.), 523(M⁺, 40%), 304 (30%), 101 (100%), and 72 (65%); HRMS for C₂₃H₃₅NO₄ ¹¹⁶Snrequires 523.1922 found 523.1920.

(c)(3-((2,5-Dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(thiophen-2-yl)iodoniumtrifluoroacetate (12)

To a solution of diacetoxyiodo-2-thiophene (1.86 g, 5.60 mmol) inanhydrous dichloromethane (50 mL) was added trifluoro acetic acid (0.80mL, 10.32 mmol) dropwise at −30° C. under nitrogen. After 30 minutes,the solution was warmed to room temperature and stirred for anotherhour. When the solution was recooled to 30° C., ethyl3-tributylstannanyl benzoate (2.62 g, 5.16 mmol) was added. The solutionwas warmed to room temperature overnight. The solvent was removed invacuo and the crude material was purified by column chromatography onsilica, eluting with dichloromethane and methanol (15:1) and thenrecrystallised from acetonitrile to yield the title compound ascolourless needles (0.89 g, 32%); m.p. 118-120° C.; (Found C, 37.64; H,2.08; N, 2.51. C₁₇H₁₅₁F₃INO₆S requires C, 37.73; H, 2.05; N, 2.59%.);v_(max)/cm⁻¹(neat) 1732 (ester), 1661 (amide); δ_(H) (300 MHz, DMSO-d₆)8.97 (1H, s, H₂), 8.64 (1H, d, J 6.0 Hz, H₆), 8.32 (1H, d, J 6.0 Hz,),8.14 (1H, d, J 9.0 Hz, H₁′), 7.99 (1H, d, J 6.0 Hz, H₄′), 7.80 (1H, t, J6.0 Hz, H₅), 7.20 (1H, dd, J 9.0 Hz, J′6.0 Hz, H₃′), 2.92 (4H, s,COCH₂×2); δ_(c) (75 MHz, DMSO-d₆) 170.1 (OCO), 160.7 (NCO), 141.2 (C₁),141.0 (C₂), 137.8 (C₆), 135.7 (C₂′), 135.2 (C₄), 133.8 (C₄′), 132.2(C₃′), 127.5 (C₅), 120.4 (C₁′), 101.6 (C₃), 26.0 (COCH₂); m/z (ES.I.),429 (MH⁺, 20%), 428 (M⁺, 100%), and 331 (45%); HRMS for C₁₅H₁₁INO₄S⁺requires 427.9448 found 427.9447.

Under the reaction conditions of Example 2 above, trace amounts ofN-succinimidyl-3-fluorobenzoate were produced.

1. An iodonium compound of formula (I):

where R^(AR1) is a phenyl group, bearing at least one acylamidocarboxysubstituent; R^(AR2) is a C5-10 aryl group, optionally substituted byone or more groups selected from the group consisting of C₁₋₁₂ alkyl,C₅₋₁₂ aryl, C₃₋₁₂ heterocyclyl, ether, thioether, nitro, cyano, amine,and halo, and may be linked to a solid support or fluorous tag; and X isa counteranion.
 2. The compound according to claim 1, wherein R^(AR1)bears a single substituent which is succinimidylcarboxy.
 3. The compoundaccording to claim 1, wherein X is selected from the group consisting ofCF₃COO, TsO, MsO, NsO, TfO, BAr₄, NO₃, Br, Cl and HSO₄(−), where Arrepresents a C₅₋₂₀ aryl group.
 4. The compound according to claim 3,wherein X is CF₃COO.
 5. The compound according to claim 1, whereinR^(AR2) is a thiophenyl or furanyl.
 6. The compound according to claim5, wherein R^(AR2) is thiophen-2-yl.
 7. The compound according to claim6, wherein the thiophen-2-yl is unsubstituted.
 8. The compound accordingto claim 1, wherein R^(AR2) is phenyl.
 9. The compound according toclaim 1, wherein the optional substituents for R^(AR2) are selected fromthe group consisting of ether, thioether and amine.
 10. A method ofsynthesising a compound of formula II:

comprising fluoridating a compound of formula I of claim
 1. 11. Themethod according to claim 10, wherein the fluoridation is carried out byreacting the compound of formula I with a source of fluoride selectedfrom NaF, KF, CsF, tetraalkylammonium fluoride, or tetraalkylphosphoniumfluoride.
 12. The method according to claim 11, wherein a phase transfercatalyst is used in addition to the source of fluoride.
 13. The methodaccording to claim 11, wherein a free radical trap is also used.
 14. Amethod of synthesising a compound of formula I of claim 1 comprising thestep of reacting a compound of formula IIIa or IIIb:

with a compound of formula IVa or IVb:

wherein Q is SNR₃, B(OH)₂ or B(OR)₂, where R is C1-7 alkyl; and W isOCORW or halo, where RW is C1-4 alkyl.